BCL2Genotypes: Functional and Neurobehavioral Outcomes after Severe Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) triggers a cascade of apoptotic-related events that include BCL2 expression, a prosurvival protein in the apoptosis pathway. The purpose of this study was to use tagging single nucleotide polymorphism (tSNP) genotypes to screen the BCL2 gene to determine if genetic variability in the BCL2 gene influences outcomes in 205 patients with severe TBI. Outcomes (Glasgow Outcome Scale [GOS], Disability Rating Scale [DRS], mortality, and Neurobehavioral Rating Scale-Revised [NRS-R]) were analyzed at 3, 6, 12, and 24 months. Multivariate analysis demonstrates that there were four tSNPs of significant interest: rs17759659, rs1801018, rs7236090, and rs949037. Presence of the variant allele for rs17759659 was associated with poorer outcomes (GOS p ¼ 0.001; DRS p ¼ 0.002), higher mortality ( p ¼ 0.02; OR ¼ 4.23; CI 1.31,13.61), and worse NRS-R scores ( p ¼ 0.05). Presence of the variant allele for rs1801018 was associated with poorer outcomes (GOS p ¼ 0.02; DRS p ¼ 0.009), and mortality ( p ¼ 0.03; OR ¼ 3.86; CI 1.18,12.59). Being homozygous for the wild-type allele for rs7236090 was associated with favorable outcomes on the NRS-R ( p ¼ 0.007), while homozygosity for the variant genotype was associated with favorable outcomes on the GOS ( p ¼ 0.007) and DRS ( p ¼ 0.006). The homozygous variant for rs949037 was associated with favorable outcomes (GOS p ¼ 0.04; DRS p ¼ 0.03), and the homozygous wild-type was associated with increased mortality at 3 months ( p ¼ 0.005; OR ¼ 3.67; CI 1.08,12.49). The only finding that stood up to Bonferroni correction was rs17759659 for GOS. These data support the possibility that genetic variability for pro-survival proteins, particularly genetic variation in the BCL2 gene, impacts outcomes after severe TBI.

Re-Orientation of Clinical Research in Traumatic Brain Injury: Report of an International Workshop on Comparative Effectiveness Research

“…The relevance of genetics may be seen by the observation that recovery is poorer in patients with stroke or TBI who have the APOE e4 allele than in those who do not have this allele (Alexander et al, 2007). Other genes for which evidence exists for associations with outcomes are the TP53, COMT, DRD2, CAC-NA1A, and BCL2 genotypes ( Jordan, 2007;Zangrilli Hoh et al, 2010).…”

Genetic Variations Associated with Brain Disorders: Focus on Synaptic Plasticity and Apoptosis Regulatory Genes in Schizophrenia, Posttraumatic Stress Disorder and Ischemic Stroke

“…Opposite to the BAX gene rs1057369 SNP, the BCL2 gene rs1801018 and rs956572 SNPs have been intensively studied in different conditions. The rs1801018 SNP was mostly found to be associated with oncological disorders [89][90][91][92] as well as with poorer clinical outcomes and mortality in patients with traumatic brain injury [93]. The rs956572 SNP was shown to associate with the risk for developing bipolar disorder and was nominated as modulator of the expression of Bcl-2 protein and cellular vulnerability to apoptosis [94].…”

Genetic polymorphism at BCL2 as a predictor for rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone efficacy in patients with diffuse large B-cell lymphoma

“…Some studies reported associations of these SNPS with other biological outcomes and human disorders. [12][13][14][15] Rs7226979 is significantly associated with the risk of non-obstructive azoospermia.…”

“…15 Currently, most clinically applied predictive markers are based on tumor material; however, the discovery of host related prognostic and predictive factors is also important. Compared to genetic analysis of the tumor, the patient's constitutional genetic profile is relatively easy to obtain, and can be assessed before treatment is started.…”